Fig. 1. Signal peptide peptidase is a presenilin-like aspartyl protease. Human SPP has seven TM domains with the N-terminus facing the ER lumen and the C-terminus facing the cytoplasm. The active site motif YD is located in the center of TM domain 4, and the corresponding active site motif LGXGD is located in the center of adjacent TM domain 5. Human PS has eight TM domains with both N- and C-termini facing the cytoplasm. The corresponding active motifs are located in the center of TM domains 6 and 7 with reverse orientation. PS and SPP are involved in intramembrane proteolysis of type I and II substrates, respectively. Conserved PALL (SPP) and PALP (PS) motifs in the C-terminus are also shown.